15-Lipoxygenase-2 (ALOX15B) is an arachidonic acid metabolizing enzyme that has been implicated as a functional tumor suppressor for prostate cancer. The expression and activity of 15-LOX-2 are frequently suppressed during carcinogenesis of prostate, lung, esophageal and sebaceous gland. Based on the observations that restoration of 15-LOX-2 expression in prostate cancer cells inhibited both DNA replication and tumor development, 15-LOX-2 has been proposed as a functional tumor suppressor for prostate cancer. However, it is unknown how 15-LOX-2 expression and functionality are suppressed in cancerous cells, the mechanism involved for 15-LOX-2 to suppress tumor formation, and whether or not 15-LOX-2 can be utilized as a therapeutic agent or an effector to attenuate or inhibit the disease progression. Our long term goal is to elucidate the role of 15-LOX-2 in prostate cancer and to develop targeted approach for prevention and treatment of cancer. The specific hypothesis behind the proposed research is that 15-LOX-2 is a major regulatory switch controlling tumor dormancy, and that loss of 15-LOX-2 contributes to prostate carcinogenesis. The specific aims are: 1) to characterize ALOX15B mutations/polymorphisms in human prostate cancer using mutational and sequencing analysis of human ALOX15B loci in prostate tumor cells; 2) to determine the functionality of tumor cell (tc)-15-LOX-2 in prostate cancer biology through a gain of function by expression of recombinant tc-15-LOX-2 protein or loss of function by ablation of endogenous expression of tc-15-LOX-2 using RNAi approach; and 3) to delineate the mechanistic link between 15-LOX-2 and VEGF expression using promoter deletion and mutation analysis. The proposed studies will significantly advance our understanding about 15-LOX-2, a functional tumor suppressor, in prostate cancer biology. The proposed studies will lead to a better understanding of the loss of 15-LOX-2 functionality as a tumor suppressor during prostate carcinogenesis, and the mechanism by which 15-LOX-2 keeps tumor suppressed. PUBLIC HEALTH RELEVANCE: 15-Lipoxygenase-2 (ALOX15B) is a newly identified functional tumor suppressor whose functionality is frequently suppressed in prostate cancer. The goals of this proposal are to examine the mutations/polymorphisms of 15-LOX-2 gene loci, to determine the routes of 15-LOX-2 suppression in prostate cancer, and to elucidate how 15-LOX-2 keeps prostate tumor suppressed in a latent stage. The studies will improve the risk assessment, detection, prevention, and treatment of prostate cancer, a major threat to public health and a financial burden to Medicare.